Solid forms of macrocyclic compounds, salts and formulations thereof, and methods of preparing and using the same

Abstract

The present disclosure relates to solid forms of Compound 1, or a pharmaceutically acceptable form thereof, a pharmaceutically acceptable salt of Compound 1, or pharmaceutically acceptable solvate thereof, pharmaceutical compositions comprising the same, methods of preparing the same, and methods of treating cancer dependent on a farnesylated protein, using the same.

What is claimed is: 
     
         1 . A solid form comprising Compound 1, or a pharmaceutically acceptable salt and/or a pharmaceutically acceptable solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein the solid form is crystalline. 
     
     
         2 . The solid form of  claim 1 , wherein the solid form comprises a free base of the Compound 1 or the pharmaceutically acceptable solvate thereof. 
     
     
         3 . The solid form of  claim 1 , wherein the solid form is a non-solvate of the Compound 1 or the pharmaceutically acceptable salt thereof. 
     
     
         4 . The solid form of  claim 1 , wherein the solid form is the pharmaceutically acceptable solvate of the Compound 1 or the pharmaceutically acceptable salt thereof, comprising (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable solvent. 
     
     
         5 . The solid form of  claim 4 , wherein the pharmaceutically acceptable solvate is selected from the group consisting of: a hydrate, an iso-butyl acetate solvate, an iso-propyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, and an acetonitrile solvate, and combinations thereof. 
     
     
         6 . The solid form of  claim 5 , wherein the pharmaceutically acceptable solvate comprises (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) the pharmaceutically acceptable solvent, in a molar ratio in the range of about 2:1 to about 1:2. 
     
     
         7 . The solid form of  claim 6 , wherein the pharmaceutically acceptable solvate is a hydrate. 
     
     
         8 . The solid form of  claim 7 , wherein the hydrate comprises (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) water, in a molar ratio in the range of about 2:1 to about 1:2. 
     
     
         9 . The solid form of  claim 1 , wherein the solid form is a crystalline, free base, hemi-hydrate of the Compound 1. 
     
     
         10 . The solid form of  claim 9 , wherein the solid form is Compound 1 (Form 1). 
     
     
         11 . The solid form of  claim 9 , which is characterized by an X-ray power diffraction (XRPD) pattern, when measured using Cu Kα radiation, comprising peaks at approximately 9.0, 12.8, 16.6, and 18.4° 2θ. 
     
     
         12 . The solid form of  claim 1 , wherein the solid form comprises the pharmaceutically acceptable salt of the Compound 1 or the pharmaceutically acceptable solvate thereof. 
     
     
         13 . The solid form of  claim 12 , wherein the pharmaceutically acceptable salt is a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glycolate salt, a 1-hydroxy-2-naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a tartrate salt, or a tosylate salt. 
     
     
         14 . The solid form of  claim 1 , wherein the solid form is a free base of the Compound 1 or the pharmaceutically acceptable solvate thereof. 
     
     
         15 . The solid form of  claim 11 , wherein the XRPD pattern comprises a peak selected from the group consisting of approximately 8.6, 12.0, 18.1, and 23.2°  2 θ. 
     
     
         16 . The solid form of  claim 15 , wherein the XRPD pattern comprises a peak selected from the group consisting of approximately 16.1, 17.1, 24.1, and 25.6°  2 θ. 
     
     
         17 . The solid form of  claim 9 , which is characterized by having approximately unit cell dimensions of a=15.2Å, b=7.9 Å, c=20.7 Å, α=90°, ß=107.8°, and γ=90°, and a unit cell of a space group of P2 1 . 
     
     
         18 . The solid form of  claim 9 , which exhibits a thermal (endothermic) event with an onset temperature of about 83° C. and a thermal (endothermic, melting) event with an onset temperature of about 212° C., and/or an endothermic peak at about 137° C. and at about 221° C., as characterized by differential scanning calorimetry (DSC) with a temperature ramp of about 10° C./min. 
     
     
         19 . The solid form of  claim 9 , which exhibits no weight loss upon heating below about 75° C. and a weight loss of about 1.8% upon heating from about 75° C. to about 170° C., as characterized by thermal gravimetric analysis (TGA). 
     
     
         20 . The solid form of  claim 9 , wherein the solid form has a purity of at least 98%, 98.5%, 99%, or 99.5%. 
     
     
         21 . The solid form of  claim 9 , wherein the solid form has:
 (a) a solubility of about 4.69, 5.04, and 3.67 mg/mL in simulated gastric fluid (SGF) media, at 0.5 h, 2 h, and 24 h, respectively; or   (b) a solubility of about 0.29, 0.31, and 0.33 mg/mL in fed state simulated intestinal fluid (FeSSIF) media, at 0.5 h, 2 h, and 24 h, respectively;   
       or a combination thereof. 
     
     
         22 . The solid form of  claim 1 , wherein the solid form comprises a non-solvate of the Compound 1 or the pharmaceutically acceptable salt thereof. 
     
     
         23 . The solid form of  claim 1 , wherein the solid form comprises the pharmaceutically acceptable solvate of the Compound 1 or the pharmaceutically acceptable salt thereof. 
     
     
         24 . The solid form of  claim 1 , wherein the solid form is the pharmaceutically acceptable salt of the Compound 1 or the pharmaceutically acceptable solvate thereof. 
     
     
         25 . A solid form comprising a pharmaceutically acceptable solvate of Compound 1, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 i) the pharmaceutically acceptable solvate is selected from the group consisting of: a hydrate, an iso-butyl acetate solvate, an iso-propyl acetate solvate, a tetrahydrofuran solvate, an acetone solvate, and an acetonitrile solvate, and combinations thereof; and 
 ii) the pharmaceutically acceptable solvate comprises (a) the Compound 1 or the pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable solvent, solvent are present in a molar ratio in the range of about 2:1 to about 1:2. 
 
     
     
         26 . The solid form of  claim 25 , wherein the pharmaceutically acceptable solvate is a hydrate. 
     
     
         27 . The solid form of  claim 26 , wherein the hydrate comprises (i) the Compound 1 or the pharmaceutically acceptable salt thereof, and (ii) water in a molar ratio of about 2:1 (hemi-hydrate). 
     
     
         28 . The solid form of  claim 25 , wherein the pharmaceutically acceptable salt is a benzoate salt, a besylate salt, a chloride salt, a citrate salt, a fumarate salt, a gentisate salt, a glycolate salt, a 1-hydroxy-2-naphthoate salt, a malate salt, a maleate salt, a mesylate salt, an oxalate salt, a phosphate salt, a tartrate salt, or a tosylate salt.